Publications by authors named "Eduardo Soriano"

145 Publications

ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity.

Cancers (Basel) 2021 Mar 5;13(5). Epub 2021 Mar 5.

Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.

ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.
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http://dx.doi.org/10.3390/cancers13051110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961652PMC
March 2021

Comprehensive identification of somatic nucleotide variants in human brain tissue.

Genome Biol 2021 Mar 29;22(1):92. Epub 2021 Mar 29.

Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.

Background: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.

Results: Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.

Conclusions: This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.
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http://dx.doi.org/10.1186/s13059-021-02285-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006362PMC
March 2021

Characterization of an eutherian gene cluster generated after transposon domestication identifies Bex3 as relevant for advanced neurological functions.

Genome Biol 2020 10 26;21(1):267. Epub 2020 Oct 26.

Department of Genetics, Microbiology and Statistics, Faculty of Biology, and Institut de Biomedicina (IBUB), University of Barcelona, 08028, Barcelona, Spain.

Background: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood.

Results: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes.

Conclusions: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders.
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http://dx.doi.org/10.1186/s13059-020-02172-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586669PMC
October 2020

Growth cone repulsion to Netrin-1 depends on lipid raft microdomains enriched in UNC5 receptors.

Cell Mol Life Sci 2021 Mar 23;78(6):2797-2820. Epub 2020 Oct 23.

Department of Cell Biology, Physiology and Immunology, Faculty of Biology and Institute of Neurosciences, University of Barcelona, 08028, Barcelona, Spain.

During brain development, Uncoordinated locomotion 5 (UNC5) receptors control axonal extension through their sensing of the guidance molecule Netrin-1. The correct positioning of receptors into cholesterol-enriched membrane raft microdomains is crucial for the efficient transduction of the recognized signals. However, whether such microdomains are required for the appropriate axonal guidance mediated by UNC5 receptors remains unknown. Here, we combine the use of confocal microscopy, live-cell FRAP analysis and single-particle tracking PALM to characterize the distribution of UNC5 receptors into raft microdomains, revealing differences in their membrane mobility properties. Using pharmacological and genetic approaches in primary neuronal cultures and brain cerebellar explants we further demonstrate that disrupting raft microdomains inhibits the chemorepulsive response of growth cones and axons against Netrin-1. Together, our findings indicate that the distribution of all UNC5 receptors into cholesterol-enriched raft microdomains is heterogeneous and that the specific localization has functional consequences for the axonal chemorepulsion against Netrin-1.
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http://dx.doi.org/10.1007/s00018-020-03663-zDOI Listing
March 2021

Nystatin Regulates Axonal Extension and Regeneration by Modifying the Levels of Nitric Oxide.

Front Mol Neurosci 2020 3;13:56. Epub 2020 Apr 3.

Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), University of Queensland, St Lucia Campus, Brisbane, QLD, Australia.

Nystatin is a pharmacological agent commonly used for the treatment of oral, mucosal and cutaneous fungal infections. Nystatin has also been extensively applied to study the cellular function of cholesterol-enriched structures because of its ability to bind and extract cholesterol from mammalian membranes. In neurons, cholesterol level is tightly regulated, being essential for synapse and dendrite formation, and axonal guidance. However, the action of Nystatin on axon regeneration has been poorly evaluated. Here, we examine the effect of Nystatin on primary cultures of hippocampal neurons, showing how acute dose (minutes) of Nystatin increases the area of growth cones, and chronic treatment (days) enhances axon length, axon branching, and axon regeneration post-axotomy. We describe two alternative signaling pathways responsible for the observed effects and activated at different concentrations of Nystatin. At elevated concentrations, Nystatin promotes growth cone expansion through phosphorylation of Akt; whereas, at low concentrations, Nystatin enhances axon length and regrowth by increasing nitric oxide levels. Together, our findings indicate new signaling pathways of Nystatin and propose this compound as a novel regulator of axon regeneration.
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http://dx.doi.org/10.3389/fnmol.2020.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146717PMC
April 2020

Rapid and Selective Targeting of Heterogeneous Pancreatic Neuroendocrine Tumors.

iScience 2020 Apr 25;23(4):101006. Epub 2020 Mar 25.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Design of tissue-specific contrast agents to delineate tumors from background tissues is a major unmet clinical need for ultimate surgical interventions. Bioconjugation of fluorophore(s) to a ligand has been mainly used to target overexpressed receptors on tumors. However, the size of the final targeted ligand can be large, >20 kDa, and cannot readily cross the microvasculature to meet the specific tissue, resulting in low targetability with a high background. Here, we report a small and hydrophilic phenoxazine with high targetability and retention to pancreatic neuroendocrine tumor. This bioengineered fluorophore permits sensitive detection of ultrasmall (<0.5 mm) ectopic tumors within a few seconds after a single bolus injection, highlighting every tumor in the pancreas from the surrounding healthy tissues with reasonable half-life. The knowledge-based approach and validation used to develop structure-inherent tumor-targeted fluorophores have a tremendous potential to improve treatment outcome by providing definite tumor margins for image-guided surgery.
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http://dx.doi.org/10.1016/j.isci.2020.101006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139119PMC
April 2020

NCAM2 Regulates Dendritic and Axonal Differentiation through the Cytoskeletal Proteins MAP2 and 14-3-3.

Cereb Cortex 2020 May;30(6):3781-3799

Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, 08028 Barcelona, Spain.

Neural cell adhesion molecule 2 (NCAM2) is involved in the development and plasticity of the olfactory system. Genetic data have implicated the NCAM2 gene in neurodevelopmental disorders including Down syndrome and autism, although its role in cortical development is unknown. Here, we show that while overexpression of NCAM2 in hippocampal neurons leads to minor alterations, its downregulation severely compromises dendritic architecture, leading to an aberrant phenotype including shorter dendritic trees, retraction of dendrites, and emergence of numerous somatic neurites. Further, our data reveal alterations in the axonal tree and deficits in neuronal polarization. In vivo studies confirm the phenotype and reveal an unexpected role for NCAM2 in cortical migration. Proteomic and cell biology experiments show that NCAM2 molecules exert their functions through a protein complex with the cytoskeletal-associated proteins MAP2 and 14-3-3γ and ζ. We provide evidence that NCAM2 depletion results in destabilization of the microtubular network and reduced MAP2 signal. Our results demonstrate a role for NCAM2 in dendritic formation and maintenance, and in neural polarization and migration, through interaction of NCAM2 with microtubule-associated proteins.
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http://dx.doi.org/10.1093/cercor/bhz342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233011PMC
May 2020

SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L.

Cell Death Dis 2020 02 3;11(2):82. Epub 2020 Feb 3.

Cell Signaling and Apoptosis Group, Vall d'Hebron Research Institute (VHIR), 08035, Barcelona, Spain.

The long isoform of Fas apoptosis inhibitory molecule (FAIM-L) is a neuron-specific death receptor antagonist that modulates apoptotic cell death and mechanisms of neuronal plasticity. FAIM-L exerts its antiapoptotic action by binding to X-linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspases, which are the main effectors of apoptosis. XIAP levels are regulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents the ubiquitination and degradation of the latter, thereby allowing it to inhibit caspase activation. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR) in hippocampal long-term depression (LTD). The molecular mechanism of action exerted by FAIM-L is unclear since the consensus binding motifs are still unknown. Here, we performed a two-hybrid screening to discover novel FAIM-L-interacting proteins. We found a functional interaction of SIVA-1 with FAIM-L. SIVA-1 is a proapoptotic protein that has the capacity to interact with XIAP. We describe how SIVA-1 regulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination, caspase-3 activation and neuronal death. Furthermore, we report that SIVA-1 plays a role in receptor internalization in synapses. SIVA-1 is upregulated upon chemical LTD induction, and it modulates AMPAR internalization via non-apoptotic activation of caspases. In summary, our findings uncover SIVA-1 as new functional partner of FAIM-L and demonstrate its role as a regulator of caspase activity in synaptic function.
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http://dx.doi.org/10.1038/s41419-020-2282-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997380PMC
February 2020

Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy.

Prog Neurobiol 2020 03 20;186:101743. Epub 2019 Dec 20.

Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, 08028, Barcelona, Spain; Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain; ICREA Academia, 08010, Barcelona, Spain. Electronic address:

Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-β (Aβ) pathology in Alzheimer's Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aβ-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aβ pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101743DOI Listing
March 2020

Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation.

Exp Neurol 2020 01 8;323:113095. Epub 2019 Nov 8.

Stem Cell and Regenerative Medicine Laboratory, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Neurosciences Institute, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova 143, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain. Electronic address:

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.
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http://dx.doi.org/10.1016/j.expneurol.2019.113095DOI Listing
January 2020

Reverse order method for teaching cataract surgery to residents.

BMJ Open Ophthalmol 2019 9;4(1):e000190. Epub 2019 Aug 9.

Ophthalmology, Universidade Federal de Sao Paulo Escola Paulista de Medicina, Sao Paulo, Brazil.

Objective: To implement a method to train residents in the performance of phacoemulsification surgery, with the steps completed in reverse chronological order and with the easiest step being undertaken first.

Methods And Analysis: We created a method for training ophthalmology residents in which we taught phacoemulsification surgery in a series of steps learnt in reverse order. Each resident advanced through the teaching modules only after being approved in the final step and then progressed to the complete performance of surgeries. We analysed the rates of complications in the 2 years after introducing the new method.

Results: The new method allowed for a standardised approach that enabled replicated teaching of phacoemulsification regardless of instructor or student. After implementing the new method, residents performed 1817 phacoemulsification surgeries in the first year and 1860 in the second year, with posterior capsule rupture rates of 8.42% and 7.9%, respectively.

Conclusions: Teaching residents to perform the steps of phacoemulsification in a standardised reverse order resulted in low rates of complications.
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http://dx.doi.org/10.1136/bmjophth-2018-000190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711465PMC
August 2019

Reversible silencing of endogenous receptors in intact brain tissue using 2-photon pharmacology.

Proc Natl Acad Sci U S A 2019 07 13;116(27):13680-13689. Epub 2019 Jun 13.

Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain;

The physiological activity of proteins is often studied with loss-of-function genetic approaches, but the corresponding phenotypes develop slowly and can be confounding. Photopharmacology allows direct, fast, and reversible control of endogenous protein activity, with spatiotemporal resolution set by the illumination method. Here, we combine a photoswitchable allosteric modulator (alloswitch) and 2-photon excitation using pulsed near-infrared lasers to reversibly silence metabotropic glutamate 5 (mGlu) receptor activity in intact brain tissue. Endogenous receptors can be photoactivated in neurons and astrocytes with pharmacological selectivity and with an axial resolution between 5 and 10 µm. Thus, 2-photon pharmacology using alloswitch allows investigating mGlu-dependent processes in wild-type animals, including synaptic formation and plasticity, and signaling pathways from intracellular organelles.
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http://dx.doi.org/10.1073/pnas.1900430116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613107PMC
July 2019

Cholesterol Depletion Regulates Axonal Growth and Enhances Central and Peripheral Nerve Regeneration.

Front Cell Neurosci 2019 12;13:40. Epub 2019 Feb 12.

Department of Cell Biology, Physiology and Immunology, Faculty of Biology, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.

Axonal growth during normal development and axonal regeneration rely on the action of many receptor signaling systems and complexes, most of them located in specialized raft membrane microdomains with a precise lipid composition. Cholesterol is a component of membrane rafts and the integrity of these structures depends on the concentrations present of this compound. Here we explored the effect of cholesterol depletion in both developing neurons and regenerating axons. First, we show that cholesterol depletion in developing neurons from the central and peripheral nervous systems increases the size of growth cones, the density of filopodium-like structures and the number of neurite branching points. Next, we demonstrate that cholesterol depletion enhances axonal regeneration after axotomy both in a microfluidic system using dissociated hippocampal neurons and in a slice-coculture organotypic model of axotomy and regeneration. Finally, using axotomy experiments in the sciatic nerve, we also show that cholesterol depletion favors axonal regeneration . Importantly, the enhanced regeneration observed in peripheral axons also correlated with earlier electrophysiological responses, thereby indicating functional recovery following the regeneration. Taken together, our results suggest that cholesterol depletion is able to promote axonal growth in developing axons and to increase axonal regeneration and both in the central and peripheral nervous systems.
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http://dx.doi.org/10.3389/fncel.2019.00040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379282PMC
February 2019

Differential accumulation of Tau phosphorylated at residues Thr231, Ser262 and Thr205 in hippocampal interneurons and its modulation by Tau mutations (VLW) and amyloid-β peptide.

Neurobiol Dis 2019 05 13;125:232-244. Epub 2018 Dec 13.

Department of Cell Biology, Physiology and Immunology, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.; Vall d'Hebron Institute of Research, Barcelona, Spain.. Electronic address:

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated Tau protein (P-Tau). Our recent data showed a differential accumulation of Tau protein phosphorylated at residue Thr231 (pThr231) in distinct hippocampal neurons in VLW mice-a model that overexpresses mutated human Tau. Here we demonstrate that, in VLW mice, the accumulation of human P-Tau in pyramidal cells induces the phosphorylation of murine Tau at residue Thr231 in hippocampal interneurons. In addition, we show that pSer262 and pThr205 Tau are present specifically in the soma of some hippocampal interneurons in control mice. Analysis of J20 mice-a model that accumulates Aβ-and of VLW animals showed that the density of hippocampal interneurons accumulating pThr205 Tau is lower in VLW mice than in controls. In contrast, the density of interneurons accumulating pThr205 Tau in J20 mice was increased compared to controls in hippocampal regions with a higher Aβ plaque load, thereby suggesting that pThr205 Tau is induced by Aβ. No significant differences were found between the density of hippocampal interneurons positive for pSer262 Tau in VLW or J20 mice compared to control animals. We also show that pSer262 and pThr205 Tau are present in the soma of some hippocampal interneurons containing Parvalbumin, Calbindin or Calretinin in control, VLW, and J20 mice. Moreover, our results reveal that some interneurons in human hippocampi of cases of AD and control cases accumulate pSer262 and pThr205 Tau. Taken together, these data point to a specific role of pSer262 and pThr205 Tau in the soma of hippocampal interneurons in control and pathological conditions.
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http://dx.doi.org/10.1016/j.nbd.2018.12.006DOI Listing
May 2019

Syntaxin-1/TI-VAMP SNAREs interact with Trk receptors and are required for neurotrophin-dependent outgrowth.

Oncotarget 2018 Nov 13;9(89):35922-35940. Epub 2018 Nov 13.

Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.

SNARE proteins are essential components of the machinery that regulates vesicle trafficking and exocytosis. Their role is critical for the membrane-fusion processes that occur during neurotransmitter release. However, research in the last decade has also unraveled the relevance of these proteins in membrane expansion and cytoskeletal rearrangements during developmental processes such as neuronal migration and growth cone extension and attraction. Neurotrophins are neurotrophic factors that are required for many cellular functions throughout the brain, including neurite outgrowth and guidance, synaptic formation, and plasticity. Here we show that neurotrophin Trk receptors form a specific protein complex with the t-SNARE protein Syntaxin 1, both and . We also demonstrate that blockade of Syntaxin 1 abolishes neurotrophin-dependent growth of axons in neuronal cultures and decreases exocytotic events at the tip of axonal growth cones. 25-kDa soluble N-ethylmaleimide-sensitive factor attachment protein and Vesicle-associated membrane protein 2 do not participate in the formation of this SNARE complex, while tetanus neurotoxin-insensitive vesicle-associated membrane protein interacts with Trk receptors; knockdown of this (v) SNARE impairs Trk-dependent outgrowth. Taken together, our results support the notion that an atypical SNARE complex comprising Syntaxin 1 and tetanus neurotoxin-insensitive vesicle-associated membrane protein is required for axonal neurotrophin function.
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http://dx.doi.org/10.18632/oncotarget.26307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267591PMC
November 2018

Human Brain Single Nucleotide Polymorphism: Validation of DNA Sequencing.

J Alzheimers Dis Rep 2018 May 31;2(1):103-109. Epub 2018 May 31.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.

Genetic factors may be involved in the onset of neurodegenerative diseases like Alzheimer's disease. In the case of the familial type, the disease is due to an inherited mutation at specific sites in three genes. Also, there are some genetic risk factors that facilitate the development of sporadic Alzheimer's disease. All of these genetic analyses were performed using blood samples as a source of DNA. However, the presence of somatic mutations in the brain can be identified only using brain samples. In this review, we comment on a method that correctly identifies single nucleotide variations in the human brain and that can be used to validate high-through sequencing techniques. This method involves selective enrichment of the DNA population bearing the nucleotide variations, thereby facilitating posterior validation of the data by Sanger's sequencing.
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http://dx.doi.org/10.3233/ADR-170039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159612PMC
May 2018

NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity.

J Alzheimers Dis 2018 ;65(4):1469-1483

Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Spain.

Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a culture medium containing 100μM glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3.
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http://dx.doi.org/10.3233/JAD-180668DOI Listing
August 2019

A conserved role for Syntaxin-1 in pre- and post-commissural midline axonal guidance in fly, chick, and mouse.

PLoS Genet 2018 06 18;14(6):e1007432. Epub 2018 Jun 18.

Department of Cell Biology, Physiology and Immunology, Faculty of Biology and Institute of Neurosciences, University of Barcelona, Barcelona, Spain.

Axonal growth and guidance rely on correct growth cone responses to guidance cues. Unlike the signaling cascades that link axonal growth to cytoskeletal dynamics, little is known about the crosstalk mechanisms between guidance and membrane dynamics and turnover. Recent studies indicate that whereas axonal attraction requires exocytosis, chemorepulsion relies on endocytosis. Indeed, our own studies have shown that Netrin-1/Deleted in Colorectal Cancer (DCC) signaling triggers exocytosis through the SNARE Syntaxin-1 (STX1). However, limited in vivo evidence is available about the role of SNARE proteins in axonal guidance. To address this issue, here we systematically deleted SNARE genes in three species. We show that loss-of-function of STX1 results in pre- and post-commissural axonal guidance defects in the midline of fly, chick, and mouse embryos. Inactivation of VAMP2, Ti-VAMP, and SNAP25 led to additional abnormalities in axonal guidance. We also confirmed that STX1 loss-of-function results in reduced sensitivity of commissural axons to Slit-2 and Netrin-1. Finally, genetic interaction studies in Drosophila show that STX1 interacts with both the Netrin-1/DCC and Robo/Slit pathways. Our data provide evidence of an evolutionarily conserved role of STX1 and SNARE proteins in midline axonal guidance in vivo, by regulating both pre- and post-commissural guidance mechanisms.
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http://dx.doi.org/10.1371/journal.pgen.1007432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029812PMC
June 2018

NEK7 regulates dendrite morphogenesis in neurons via Eg5-dependent microtubule stabilization.

Nat Commun 2018 06 13;9(1):2330. Epub 2018 Jun 13.

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.

Organization of microtubules into ordered arrays is best understood in mitotic systems, but remains poorly characterized in postmitotic cells such as neurons. By analyzing the cycling cell microtubule cytoskeleton proteome through expression profiling and targeted RNAi screening for candidates with roles in neurons, we have identified the mitotic kinase NEK7. We show that NEK7 regulates dendrite morphogenesis in vitro and in vivo. NEK7 kinase activity is required for dendrite growth and branching, as well as spine formation and morphology. NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites. Here, Eg5 limits retrograde microtubule polymerization, which is inhibitory to dendrite growth and branching. Eg5 exerts this effect through microtubule stabilization, independent of its motor activity. This work establishes NEK7 as a general regulator of the microtubule cytoskeleton, controlling essential processes in both mitotic cells and postmitotic neurons.
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http://dx.doi.org/10.1038/s41467-018-04706-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997995PMC
June 2018

SNARE complex in axonal guidance and neuroregeneration.

Neural Regen Res 2018 Mar;13(3):386-392

Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Cientific de Barcelona; Department of Genetics, Microbiology and Statistics, School of Biology, University of Barcelona, Barcelona, Spain.

Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.
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http://dx.doi.org/10.4103/1673-5374.228710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900491PMC
March 2018

New functions of Semaphorin 3E and its receptor PlexinD1 during developing and adult hippocampal formation.

Sci Rep 2018 01 22;8(1):1381. Epub 2018 Jan 22.

Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Parc Científic de Barcelona, Barcelona, Spain.

The development and maturation of cortical circuits relies on the coordinated actions of long and short range axonal guidance cues. In this regard, the class 3 semaphorins and their receptors have been seen to be involved in the development and maturation of the hippocampal connections. However, although the role of most of their family members have been described, very few data about the participation of Semaphorin 3E (Sema3E) and its receptor PlexinD1 during the development and maturation of the entorhino-hippocampal (EH) connection are available. In the present study, we focused on determining their roles both during development and in adulthood. We determined a relevant role for Sema3E/PlexinD1 in the layer-specific development of the EH connection. Indeed, mice lacking Sema3E/PlexinD1 signalling showed aberrant layering of entorhinal axons in the hippocampus during embryonic and perinatal stages. In addition, absence of Sema3E/PlexinD1 signalling results in further changes in postnatal and adult hippocampal formation, such as numerous misrouted ectopic mossy fibers. More relevantly, we describe how subgranular cells express PlexinD1 and how the absence of Sema3E induces a dysregulation of the proliferation of dentate gyrus progenitors leading to the presence of ectopic cells in the molecular layer. Lastly, Sema3E mutant mice displayed increased network excitability both in the dentate gyrus and the hippocampus proper.
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http://dx.doi.org/10.1038/s41598-018-19794-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777998PMC
January 2018

Identification of novel Ack1-interacting proteins and Ack1 phosphorylated sites in mouse brain by mass spectrometry.

Oncotarget 2017 Nov 15;8(60):101146-101157. Epub 2017 Sep 15.

Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain.

Ack1 (activated Cdc42-associated tyrosine kinase) is a non-receptor tyrosine kinase that is highly expressed in brain. This kinase contains several protein-protein interaction domains and its action is partially regulated by phosphorylation. As a first step to address the neuronal functions of Ack1, here we screened mouse brain samples to identify proteins that interact with this kinase. Using mass spectrometry analysis, we identified new putative partners for Ack1 including cytoskeletal proteins such as Drebrin or MAP4; adhesion regulators such as NCAM1 and neurabin-2; and synapse mediators such as SynGAP, GRIN1 and GRIN3. In addition, we confirmed that Ack1 and CAMKII both co-immunoprecipitate and co-localize in neurons. We also identified that adult and P5 samples contained the phosphorylated residues Thr 104 and Ser 825, and only P5 samples contained phosphorylated Ser 722, a site linked to cancer and interleukin signaling when phosphorylated. All these findings support the notion that Ack1 could be involved in neuronal plasticity.
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http://dx.doi.org/10.18632/oncotarget.20929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731862PMC
November 2017

Validation of Suspected Somatic Single Nucleotide Variations in the Brain of Alzheimer's Disease Patients.

J Alzheimers Dis 2017 ;56(3):977-990

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.

Next-generation sequencing techniques and genome-wide association study analyses have provided a huge amount of data, thereby enabling the identification of DNA variations and mutations related to disease pathogenesis. New techniques and software tools have been developed to improve the accuracy and reliability of this identification. Most of these tools have been designed to discover and validate single nucleotide variants (SNVs). However, in addition to germ-line mutations, human tissues bear genomic mosaicism, which implies that somatic events are present only in low percentages of cells within a given tissue, thereby hindering the validation of these variations using standard genetic tools. Here we propose a new method to validate some of these somatic mutations. We combine a recently developed software with a method that cuts DNA by using restriction enzymes at the sites of the variation. The non-cleaved molecules, which bear the SNV, can then be amplified and sequenced using Sanger's technique. This procedure, which allows the detection of alternative alleles present in as few as 10% of cells, could be of value for the identification and validation of low frequency somatic events in a variety of tissues and diseases.
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http://dx.doi.org/10.3233/JAD-161053DOI Listing
February 2018

SNARE proteins play a role in motor axon guidance in vertebrates and invertebrates.

Dev Neurobiol 2017 09 12;77(8):963-974. Epub 2017 Feb 12.

Institut de Recerca Biomèdica de Barcelona (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, 08028, Spain.

Axonal growth and guidance rely on correct growth cone responses to guidance cues, both in the central nervous system (CNS) and in the periphery. Unlike the signaling cascades that link axonal growth to cytoskeletal dynamics, little is known about the cross-talk mechanisms between guidance and membrane dynamics and turnover in the axon. Our studies have shown that Netrin-1/deleted in colorectal cancer signaling triggers exocytosis through the SNARE Syntaxin-1 (STX-1) during the formation of commissural pathways. However, limited in vivo evidence is available about the role of SNARE proteins in motor axonal guidance. Here we show that loss-of-function of SNARE complex members results in motor axon guidance defects in fly and chick embryos. Knock-down of Syntaxin-1, VAMP-2, and SNAP-25 leads to abnormalities in the motor axon routes out of the CNS. Our data point to an evolutionarily conserved role of the SNARE complex proteins in motor axon guidance, thereby pinpointing an important function of SNARE proteins in axonal navigation in vivo. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 963-974, 2017.
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http://dx.doi.org/10.1002/dneu.22481DOI Listing
September 2017

FAIM-L regulation of XIAP degradation modulates Synaptic Long-Term Depression and Axon Degeneration.

Sci Rep 2016 10 21;6:35775. Epub 2016 Oct 21.

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain.

Caspases have recently emerged as key regulators of axonal pruning and degeneration and of long-term depression (LTD), a long-lasting form of synaptic plasticity. However, the mechanism underlying these functions remains unclear. In this context, XIAP has been shown to modulate these processes. The neuron-specific form of FAIM protein (FAIM-L) is a death receptor antagonist that stabilizes XIAP protein levels, thus preventing death receptor-induced neuronal apoptosis. Here we show that FAIM-L modulates synaptic transmission, prevents chemical-LTD induction in hippocampal neurons, and thwarts axon degeneration after nerve growth factor (NGF) withdrawal. Additionally, we demonstrate that the participation of FAIM-L in these two processes is dependent on its capacity to stabilize XIAP protein levels. Our data reveal FAIM-L as a regulator of axonal degeneration and synaptic plasticity.
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http://dx.doi.org/10.1038/srep35775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073314PMC
October 2016

Corrigendum: FIB/SEM technology and high-throughput 3D reconstruction of dendritic spines and synapses in GFP-labeled adult-generated neurons.

Front Neuroanat 2016 18;10:100. Epub 2016 Oct 18.

Developmental Neurobiology and Regeneration Unit, Department of Cell Biology, Immunology and Neurosciences and Barcelona Science Park, University of BarcelonaBarcelona, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos IIIMadrid, Spain; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR)Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats AcademiaBarcelona, Spain.

[This corrects the article on p. 60 in vol. 9, PMID: 26052271.].
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http://dx.doi.org/10.3389/fnana.2016.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067301PMC
October 2016

The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy.

Neurobiol Aging 2017 01 15;49:40-51. Epub 2016 Sep 15.

Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain; Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain. Electronic address:

Alzheimer's disease (AD), the most common cause of dementia nowadays, has been linked to alterations in the septohippocampal pathway (SHP), among other circuits in the brain. In fact, the GABAergic component of the SHP, which controls hippocampal rhythmic activity crucial for learning and memory, is altered in the J20 mouse model of AD-a model that mimics the amyloid pathology of this disease. However, AD is characterized by another pathophysiological hallmark: the hyperphosphorylation and aggregation of the microtubule-associated protein Tau. To evaluate whether tauopathies alter the GABAergic SHP, we analyzed transgenic mice expressing human mutated Tau (mutations G272V, P301L, and R406W, VLW transgenic strain). We show that pyramidal neurons, mossy cells, and some parvalbumin (PARV)-positive hippocampal interneurons in 2- and 8-month-old (mo) VLW mice accumulate phosphorylated forms of Tau (P-Tau). By tract-tracing studies of the GABAergic SHP, we describe early-onset deterioration of GABAergic septohippocampal (SH) innervation on PARV-positive interneurons in 2-mo VLW mice. In 8-mo animals, this alteration was more severe and affected mainly P-Tau-accumulating PARV-positive interneurons. No major loss of GABAergic SHP neurons or PARV-positive hippocampal interneurons was observed, thereby indicating that this decline is not caused by neuronal loss but by the reduced number and complexity of GABAergic SHP axon terminals. The decrease in GABAergic SHP described in this study, targeted onto the PARV-positive/P-Tau-accumulating inhibitory neurons in the hippocampus, establishes a cellular correlation with the dysfunctions in rhythmic neuronal activity and excitation levels in the hippocampus. These dysfunctions are associated with the VLW transgenic strain in particular and with AD human pathology in general. These data, together with our previous results in the J20 mouse model, indicate that the GABAergic SHP is impaired in response to both amyloid-β and P-Tau accumulation. We propose that alterations in the GABAergic SHP, together with a dysfunction of P-Tau-accumulating PARV-positive neurons, contribute to the cognitive deficits and altered patterns of hippocampal activity present in tauopathies, including AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.09.006DOI Listing
January 2017

Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells.

Cereb Cortex 2016 10;26(11):4282-4298

Developmental Neurobiology and Regeneration Unit, Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona 08028, Spain.

Significance Statement: The extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders.
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http://dx.doi.org/10.1093/cercor/bhw216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066826PMC
October 2016

Non-centrosomal nucleation mediated by augmin organizes microtubules in post-mitotic neurons and controls axonal microtubule polarity.

Nat Commun 2016 07 13;7:12187. Epub 2016 Jul 13.

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.

Neurons display a highly polarized microtubule network that mediates trafficking throughout the extensive cytoplasm and is crucial for neuronal differentiation and function. In newborn migrating neurons, the microtubule network is organized by the centrosome. During neuron maturation, however, the centrosome gradually loses this activity, and how microtubules are organized in more mature neurons remains poorly understood. Here, we demonstrate that microtubule organization in post-mitotic neurons strongly depends on non-centrosomal nucleation mediated by augmin and by the nucleator γTuRC. Disruption of either complex not only reduces microtubule density but also microtubule bundling. These microtubule defects impair neurite formation, interfere with axon specification and growth, and disrupt axonal trafficking. In axons augmin does not merely mediate nucleation of microtubules but ensures their uniform plus end-out orientation. Thus, the augmin-γTuRC module, initially identified in mitotic cells, may be commonly used to generate and maintain microtubule configurations with specific polarity.
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http://dx.doi.org/10.1038/ncomms12187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947180PMC
July 2016

Reelin Exerts Structural, Biochemical and Transcriptional Regulation Over Presynaptic and Postsynaptic Elements in the Adult Hippocampus.

Front Cell Neurosci 2016 30;10:138. Epub 2016 May 30.

Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona Barcelona, Spain.

Reelin regulates neuronal positioning and synaptogenesis in the developing brain, and adult brain plasticity. Here we used transgenic mice overexpressing Reelin (Reelin-OE mice) to perform a comprehensive dissection of the effects of this protein on the structural and biochemical features of dendritic spines and axon terminals in the adult hippocampus. Electron microscopy (EM) revealed both higher density of synapses and structural complexity of both pre- and postsynaptic elements in transgenic mice than in WT mice. Dendritic spines had larger spine apparatuses, which correlated with a redistribution of Synaptopodin. Most of the changes observed in Reelin-OE mice were reversible after blockade of transgene expression, thus supporting the specificity of the observed phenotypes. Western blot and transcriptional analyses did not show major changes in the expression of pre- or postsynaptic proteins, including SNARE proteins, glutamate receptors, and scaffolding and signaling proteins. However, EM immunogold assays revealed that the NMDA receptor subunits NR2a and NR2b, and p-Cofilin showed a redistribution from synaptic to extrasynaptic pools. Taken together with previous studies, the present results suggest that Reelin regulates the structural and biochemical properties of adult hippocampal synapses by increasing their density and morphological complexity and by modifying the distribution and trafficking of major glutamatergic components.
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http://dx.doi.org/10.3389/fncel.2016.00138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884741PMC
June 2016